Anthracycline Free Regimens in High Risk Acute Promyelocytic Leukemia: A Comprehensive Review

Acute Promyelocytic Leukemia (APL), a distinct subtype of acute myeloid leukemia, has transitioned from a highly fatal to a highly curable disease due to the introduction of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). Traditionally, high-risk APL patients, defined by a white blood cell count >10 × 10?/L, were treated with anthracycline-based chemotherapy combined with ATRA. However, long-term toxicities, particularly cardiotoxicity and secondary malignancies, have driven exploration into anthracycline-free regimens. Emerging evidence from randomised trials such as AML17 and MD Anderson studies demonstrate that ATRA+ATO, with adjunctive cytoreduction using Gemtuzumab Ozogamicin (GO) or hydroxyurea, achieves outcomes comparable to standard chemotherapy even in high-risk patients. Real-world data further validate the efficacy, safety and feasibility of these regimens, especially in resource-limited settings where oral ATO formulations improve accessibility. These regimens offer significantly reduced cardiotoxicity, myelosuppression and hospitalisation, enhancing patient quality of life. Nevertheless, challenges such as early mortality, optimal cytoreduction strategy and long-term toxicity of ATO persist. Guidelines from ELN, NCCN and GIMEMA now endorse ATRA+ATO-based approaches in high-risk APL. Future directions include integration of Minimal Residual Disease (MRD) monitoring oral ATO and artificial intelligence-driven personalization. This review highlights a paradigm shift in APL management, advocating for a move towards chemotherapy-free regimens that align curative potential with survivorship and quality-of-life goals in high-risk APL.